Requested is a Scientist Development Award for Clinicians from the ADAMHA to investigate at a preclinical and clinical level two neurochemical [noradrenaline (NA), serotonin (5HT)] systems which have consistently been implicated in the pathogenesis of panic disorder (PD). An integration of preclinical and clinical studies provides a means for delineating the developmental origins and subsequent panic-relevant adult manifestations of NA and 5-HT abnormalities. Preclinical primate studies, taking advantage of random subject assignment, systematically controlled early experiences and access to repeated CSF measures, aim to assess the putative relationship between adult PD and childhood separation anxiety in humans. Research is proposed to test the hypothesis that early disruptions in maternal-infant attachment in nonhuman primates may produce NA and 5-HT neurotransmitter changes which model those observed in adults with PD. These studies, built upon previous findings that adult primates raised by mothers under conditions of variable foraging demand (VFD) show adverse affective and social development, will assess responses to putative NA and 5-HT probes both in developing and adult primates. Specifically, in comparison to control subjects, VFD subjects will show a type of noradrenergic abnormality -- hypersensitivity to the alpha-2 antagonist, yohimbine, and show serotonergic abnormality as reflected by responses to the putative serotonin agonist, mCPP. Such findings would parallel responses of adult PD patients. Clinical studies will expand upon the documented role of noradrenergic abnormalities in panic through the delineation of the hypothesized role of serotonergic abnormality and its noradrenergic effects. Clinical studies will focus on the ability of chronic and successful treatment with selective serotonin reuptake inhibitors (SSRI's) to reduce NA activity. As a further reflection of the 5-HT/NA interaction, growth hormone responses following challenge with the alpha- 2 agonist, clonidine, will be studied before, during and after SSRI treatment. Failure of successful SSRI treatment to normalize, or evidence in remitted unmedicated PD patients of persistent, blunted GH response to clonidine, typical of untreated panic patients, would support the hypothesis that the blunted GH response to clonidine is a trait characteristic of PD patients. The unifying goal of the proposal is to develop, through an integration of clinical and preclinical studies, an understanding of the development and interaction of 5-HT and NA function as pertains to PD.
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